Antimetabolites have been used for a number of years as chemotherapeutic agents in the treatment of cancer. One such drug, methotrexate, is now one of the most widely used anticancer drugs; and many other compounds in the folic acid family have been synthesized, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level; they inhibit such enzymes as dihydrofolate reductase, folyl polyglutamate synthetase, glycinamide ribonucleotide formyltransferase and thymidylate synthase.
More recently, a series of 4-hydroxypyrrolo[2,3-d]pyrimidin-L-glutamic acid derivatives have been disclosed and shown to be particularly useful antifolate drugs. See, for example, U.S. Pat. Nos. 4,966,206; 5,028,608; 5,106,974; and 4,997,838. However the synthetic route for the preparation of these compounds has not yet been optimized.
The present invention provides improved processes for the preparation of 4-hydroxy-5-substituted-ethynylpyrrolo[2,3-d]pyrimidine intermediates and 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives which are useful as antifolate drugs.